Thiazole, imidazole and oxazole compounds and treatments of disorders associated with protein aging

ABSTRACT

Provided are, among other things, compounds of formula I or IA,

This patent application is a divisional of U.S. patent application Ser.No. 09/766,547, filed Jan. 19, 2001, which claims the benefit of U.S.Patent Application 60/176,995, filed Jan. 19, 2000; U.S. PatentApplication 60/183,274, filed Feb. 17, 2000; U.S. Patent Application60/259,291, filed Dec. 29, 2000; U.S. Patent Application 60/259,237,filed Jan. 2, 2001; U.S. Patent Application 60/259,107, filed Dec. 29,2000; U.S. Patent Application 60/259,239, filed Jan. 2, 2001. Thecontents of these applications are each incorporated herein by referencein their entirety.

The present invention relates to methods for treating certain fibroticdiseases or other indications.

Glucose and other sugars react with proteins by a non-enzymatic,post-translational modification process called non-enzymaticglycosylation. At least a portion of the resulting sugar-derivedadducts, called advanced glycosylation end products (AGEs), mature to amolecular species that is very reactive, and can readily bind to aminogroups on adjacent proteins, resulting in the formation of AGEcross-links between proteins. Recently a number of classes of compoundshave been identified whose members inhibit the formation of thecross-links, or in some cases break the cross-links. These compoundsinclude, for example, the thiazolium compounds described in U.S. Pat.No. 5,853,703. As AGEs, and particularly the resulting cross-links, arelinked to several degradations in body function linked with diabetes orage, these compounds have been used, with success, in animal models forsuch indications. These indications include loss of elasticity in bloodvasculature, loss of kidney function and retinopathy.

Now, as part of studies on these compounds, it has been identified thatthese compounds inhibit the formation of bioactive agents, such asgrowth factors and inflammatory mediators, that are associated with anumber of indications. These agents include vascular endothelial growthfactor (VEGF) and TGF[beta]. As a result, a number of new indicationshave been identified for treatment with agents that inhibit theformation of, or more preferably break, AGE-mediated cross-links. It isnot unreasonable to infer that the effects seen are due to the removalof AGE-related molecules that provide a stimulus for the production orrelease of these growth factors. Removal of such molecules is believedto proceed in part due to the elimination of AGE-related cross-linksthat lock the AGE-modified proteins in place. Moreover, such compoundsalso reduce the expression of collagen in conditions associated withexcess collagen production. Regardless of the mechanism, now providedare new methods of treating a number of indications.

SUMMARY OF THE INVENTION

In one embodiment, the invention relates to a method of treating orameliorating or preventing an indication of the invention in an animal,including a human, comprising administering an effective amount of acompound of the formula I or IA,

wherein the substituent groups are as defined below. In anotherembodiment, the compound administered is a compound of formula II,

wherein the substituent groups are as defined below.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, a method and compositions aredisclosed for, among other things, in an animal, treating theindications described below and (i) improving the elasticity or reducingwrinkles of the skin, treating (ii) diabetes or treating or preventing(iii) adverse sequelae of diabetes, (iv) kidney damage, (v) damage toblood vasculature, (vi) hypertension, (vii) retinopathy, (viii) damageto lens proteins, (ix) cataracts, (x) peripheral neuropathy, or (xi)osteoarthritis. Without being bound by theory, these effects arebelieved to related to the inhibition of formation of advancedglycosylation of proteins (protein aging) and for breaking thecross-links that form between advanced glycosylation (glycation)endproducts (AGEs) or between AGEs and other proteins. The inventionfurther relates to preventing or reversing advanced glycosylationendproducts and cross-linking caused by other reactive sugars present invivo or in foodstuffs, including ribose, galactose and fructose.

In particular, the compositions comprise agents for inhibiting theformation of and reversing the pre-formed advanced glycosylation(glycation) endproducts and breaking the subsequent cross-links. Whilenot wishing to be bound by any theory, it is believed that the breakingof the pre-formed advanced glycosylation (glycation) endproducts andcross-links is a result of the cleavage of alpha-dicarbonyl-basedprotein crosslinks present in the advanced glycosylation endproducts.

Certain of the agents useful in the present invention are members of theclass of compounds known as thiazoles, others are imidazoles oroxazoles.

The compounds, and their compositions, utilized in this invention arebelieved to react with an early glycosylation product thereby preventingthe same from later forming the advanced glycosylation end products thatlead to cross-links, and thereby, to molecular or protein aging andother adverse molecular consequences. Additionally, they react withalready formed advanced glycosylation end products to reduce the amountof such products.

The ability to inhibit the formation of advanced glycosylationendproducts, and to reverse the already formed advanced glycosylationproducts in the body carries with it significant implications in allapplications where advanced glycation and concomitant molecularcrosslinking is a serious detriment. Thus, in the area of foodtechnology, for instance, the retardation of food spoilage would conferan obvious economic and social benefit by making certain foods ofmarginal stability less perishable and therefore more available forconsumers. Spoilage would be reduced as would the expense of inspection,removal, and replacement, and the extended availability of the foodscould aid in stabilizing their price in the marketplace. Similarly, inother industrial applications where the perishability of proteins is aproblem, the admixture of the agents of the present invention incompositions containing such proteins would facilitate the extendeduseful life of the same. Presently used food preservatives anddiscoloration preventatives such as sulfur dioxide, known to causetoxicity including allergy and asthma in animals, can be replaced withcompounds such as those described herein.

The present method has particular therapeutic application as theMaillard process acutely affects several of the significant proteinmasses in the body, among them collagen, elastin, lens proteins, and thekidney glomerular basement membranes. These proteins deteriorate bothwith age (hence the application of the term “protein aging”) and as aconsequence of diabetes. Accordingly, the ability to either retard orsubstantially inhibit the formation of advanced glycosylationendproducts, and to reduce the amount of cross-links formed betweenadvanced glycosylation endproducts and other proteins in the bodycarries the promise for treatment of the complications of diabetes andaging for instance, and thereby improving the quality and, perhaps,duration of animal and human life.

The present agents are also useful in the area of personal appearanceand hygiene, as they prevent, and reverse, the staining of teeth bycationic anti-microbial agents with anti-plaque properties, such aschlorhexidine.

In certain embodiments, the indications treated, ameliorated orprevented with the invention are those described or the agents are thosedescribed in U.S. Patent Application 60/176,995, filed Jan. 19, 2000;U.S. Patent Application 60/183,274, filed Feb. 17, 2000; U.S. PatentApplication 60/259,291, filed Dec. 29, 2000; U.S. Patent Application60/259,237, filed Jan. 2, 2001; U.S. Patent Application 60/259,107,filed Dec. 29, 2000; U.S. Patent Application 60/259,239, filed Jan. 2,2001.

Substituents

For Compounds of Formulas I and IA,

-   a. J is oxygen, sulfur, or N-R^(d);-   b. the carbon 2 to nitrogen bond is a double bond except when R^(c)    is oxo;-   c. the bond between carbons 4 and 5 is a single bond or a double    bond;-   d. R^(a) and R^(b) are    -   1. independently selected from hydrogen, acylamino,        acyloxyalkyl, alkanoyl, alkanoylalkyl, alkenyl, alkoxy,        alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylamino,        (C1-C3)alkylenedioxy, allyl, amino, ω-alkylenesulfonic acid,        carbamoyl, carboxy, carboxyalkyl (which alkyl can be substituted        with alkyloxyimino), cycloalkyl, dialkylamino, halo, hydroxy,        (C2-C6)hydroxyalkyl, mercapto, nitro, sulfamoyl, sulfonic acid,        alkylsulfonyl, alkylsulfinyl, alkylthio, trifluoromethyl,        morpholin-4-yl, thiomorpholin-4-yl, piperidin-1-yl,        piperazin-1-yl, Ar {wherein, consistent with the rules of        aromaticity, Ar is C₆ or C₁₀ aryl or a 5- or 6-membered        heteroaryl ring, wherein the 6-membered heteroaryl ring contains        one to three atoms of N, and the 5-membered heteroaryl ring        contains from one to three atoms of N or one atom of O or S and        zero to two atoms of N, each heteroaryl ring can be fused to a        substituted benzene, pyridine, pyrimidine, pyridazine, or        (1,2,3)triazine (wherein the ring fusion is at a carbon-carbon        double bond of Ar)}, Ar-alkyl, ArO—, ArSO₂—, ArSO—, ArS—,        ArSO₂NH—, ArNH, (N—Ar)(N-alkyl)N—, ArC(O)—, ArC(O)NH—,        ArNH—C(O)—, and (N—Ar)(N-alkyl)N—C(O)—, or together R₁ and R₂        comprise methylenedioxy-; or    -   2. together with their ring carbons form a C₆- or C₁₀-aryl fused        ring; or    -   3. together with their ring carbons form a C₅-C₇ fused        cycloalkyl ring having up to two double bonds including a fused        double bond of the containing group, which cycloalkyl ring can        be substituted by one or more of the group consisting of alkyl,        alkoxycarbonyl, amino, aminocarbonyl, carboxy, fluoro, or oxo;        or    -   4. together with their ring carbons form a fused 5- or        6-membered heteroaryl ring, wherein the 6-membered heteroaryl        ring contains one to three atoms of N, and the 5-membered        heteroaryl ring contains from one to three atoms of N or one        atom of O or S and zero to two atoms of N; or    -   5. together with their ring carbons form a fused five to eight        membered second heterocycle, wherein the fused heterocycle        consists of ring atoms selected from the group consisting of        carbon, nitrogen, oxygen, sulfur, and S(O)_(n), wherein n is 1        or 2;-   b. R^(d) is alkyl, alkenyl, hydrogen, or Ar;-   c. R^(c) is    -   1. oxo (when Δ^(2,3) is not present), or (when Δ^(2,3) is        present) hydrogen, alkyl, alkylthio, hydrogen, mercapto, amino,        amino(C₁-C₅)alkyl, amino(C₆ or C₁₀)aryl, or wherein the amino of        the last three groups can be substituted with        -   (a) Ar,        -   (b) Ar—Z—, Ar-alkyl-Z-, Ar-Z-alkyl, Ar-amino-Z-,            Ar-aminoalkyl-Z-, or Ar-oxyalkyl-Z-, wherein Z is a carbonyl            or —SO₂—,        -   (c) formyl or alkanoyl, or        -   (d) up to two alkyl,    -   2. —NHC(O)(CH₂)_(n)-D-R^(e)R^(f), wherein D is oxygen, sulfur or        nitrogen, wherein where D is nitrogen n is 0,1 or 2, but when D        is oxygen or sulfur n=1 or 2, and R^(f) is present only when D        is nitrogen,    -   wherein        -   (a) R^(e) is            -   (1) Ar; or            -   (2) a group of the formula                -   wherein E is sulfur, oxygen, or N—R^(i), and R^(g),                    R^(h) and R^(i) are independently the same as R^(a),                    R^(b) and R^(d), respectively; or            -   (3) a C₃-C₈ cycloalkyl ring having up to one double bond                with the proviso that the carbon linking the cyloalkyl                ring to D is saturated, which cycloalkyl ring can be                substituted by one or more alkyl-, alkoxycarbonyl-,                amino-, aminocarbonyl-, carboxy-, fluoro-, or                oxo-substituents; or            -   (4) a 5- or 6-membered heteroaryl ring containing at                least one and up to three atoms of N for the 6-membered                heteroaryl rings and from one to three atoms of N or one                atom of O or S and zero to two atoms of N for the                5-membered heteroaryl rings; or            -   (5) hydrogen, (C₂-C₆)hydroxyalkyl, alkanoylalkyl, alkyl,                alkoxycarbonylalkyl, alkenyl, carboxyalkyl (which alkyl                can be substituted with alkoxyimino), alkoxycarbonyl, a                group Ar¹⁰⁰ which is C₆— or C₁₀-aryl or a 5- or                6-membered, or 9- or 10-membered heteroaryl (wherein the                heteroatom is one oxygen, one sulfur or one nitrogen) or                Ar^(φ)-alkyl; and        -   (b) R^(f) is independently hydrogen, (C2-C6)hydroxyalkyl,            alkanoylalkyl, alkyl, alkoxycarbonylalkyl, alkenyl,            carboxyalkyl (which alkyl can be substituted with            alkyloxyimino), alkoxycarbonyl, Ar^(φ), or Ar^(φ)-alkyl;            wherein aryl, Ar, or Ar^(φ) can be substituted with, in            addition to any substitutions specifically noted one or more            substituents selected from the group of acylamino,            acyloxyalkyl, alkanoyl, alkanoylalkyl, alkenyl, alkoxy,            alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylamino,            (C1-C3)alkylenedioxy, alkylsulfonyl, alkylsulfinyl,            ω-alkylenesulfonic acid, alkylthio, allyl, amino, ArC(O)—,            ArC(O)NH—, carboxy, carboxyalkyl, cycloalkyl, dialkylamino,            halo, trifluoromethyl, hydroxy, (C2-C6)hydroxyalkyl,            mercapto, nitro, ArO—, Ar—, Ar-alkyl-, sulfamoyl, sulfonic            acid, 1-pyrrolidinyl, 4-[C6 or C10]arylpiperazin-1-yl-,            4-[C6 or C10] arylpiperidin-1-yl, azetidin-1-yl,            morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl,            piperidin-1-yl; and            heterocycles, except those of Ar and Ar^(φ), can be            substituted with in addition to any substitutions            specifically noted one or more substituents selected from            acylamino, alkanoyl, alkoxy, alkoxycarbonyl,            alkoxycarbonylalkyl, alkyl, (C1 to C3)alkylenedioxy,            alkylamino, alkylsulfonyl, alkylsulfinyl, alkylthio, amino,            ArC(O)—, ArO—, Ar—, Ar-alkyl, carboxy, dialkylamino, fluoro,            fluoroalkyl, difluoroalkyl, hydroxy, mercapto, oxo,            sulfamoyl, trifluoromethyl, 4-[C₆ or C₁₀]arylpiperidin-1-yl            and 4-[C₆ or C₁₀]arylpiperazin-1-yl;            or a pharmaceutically acceptable salt of said compounds,    -   with the proviso that where the compound of formula I is        administered to decrease intraocular pressure at least one        compound of formula I administered in effective amount is not a        thiazole substituted on a ring carbon with sulfonamide (the        amide of which can be substituted) that has carbonic anhydrase        inhibiting activity.        For compounds of formula II:    -   X is nitrogen or sulfur, provided that R⁴ is present only when X        is nitrogen;    -   the carbon 2 to nitrogen bond is a double bond except when R³ is        oxo;    -   the bond between carbons 4 and 5 is a single bond or a double        bond; R¹ and R²        -   are independently hydrogen, hydroxyalkyl,            (C₂-C₆)alkanoylalkyl, alkyl, alkoxycarbonylalkyl, alkenyl,            carboxyalkyl (which alkyl can be substituted with            alkyloxyimino), alkoxycarbonyl, a group Ar which is (C₆-C₁₀)            aryl or (C₅-C₉) heteroaryl (wherein the heteroatom is one            oxygen, one sulfur or one nitrogen) or Ar-alkyl, or        -   together with their ring carbons form a C₆-C₁₀ aromatic            fused ring which can be substituted by one or more halo,            amino, alkyl, sulfo, or sulfoalkyl, groups, or a C₁-C₃            alkylenedioxy group, with the proviso that when X is            nitrogen R¹ and R² do not form a C₆ fused aromatic ring, or        -   together with their ring carbons form a C₅-C₇ fused            cycloalkyl or cycloalkenyl ring having up to two double            bonds including a fused double bond of the thiazole radical,            which aliphatic ring can be substituted by one or more            amino, halo, alkyl, sulfo, sulfoalkyl, carboxy,            carboxyalkyl, or oxo groups;    -   R⁴ is lower alkyl, lower alkenyl or Ar; and    -   R³ is        -   (a) when X is S, R³ is hydrogen, oxo, alkyl, amino,            amino(C₁-C₅)alkyl or aminophenyl, wherein the amino of the            latter three groups can be substituted with:            -   (i) Ar,            -   (ii) Ar-carbonyl, Ar-alkanoyl, Ar-carbonylalkyl,                Ar-aminocarbonyl Ar-aminoalkanoyl or Ar-oxyalkanoyl or            -   (iii) formyl or alkanoyl,        -   (b) —NHC(O)(CH₂)_(n)—Y—R⁵R⁶, wherein Y is oxygen, sulfur or            nitrogen, n is 0 or 1, but n=1 when Y is oxygen or sulfur,            and R⁶ is present only when Y is nitrogen,        -    wherein R⁵ is            -   (i) Ar; or            -   (ii) a group of the formula                -   wherein R⁷, R⁸ and R⁹ are independently the same as                    R¹, R² and R⁴, Z is sulfur or nitrogen, R⁹ is                    present only when Z is nitrogen; or            -   (iii) a C₃-C₈ cycloalkyl or cycloalkenyl ring having up                to one double bond, which aliphatic ring can be                substituted by one or more amino, halo, alkyl, sulfo,                sulfoalkyl, carboxy, carboxyalkyl, or oxo groups; or            -   (iv) a 3 to 8-membered heterocyclic ring wherein the                heteroatom is one oxygen, one sulfur or one nitrogen,                which heterocyclic ring can be substituted by one or                more amino, halo, alkyl, sulfo, sulfoalkyl, carboxy,                carboxyalkyl, or oxo groups; or            -   (iv) hydrogen, hydroxyalkyl, (C₂-C₆)alkanoylalkyl,                alkyl, alkoxycarbonylalkyl, alkenyl, carboxyalkyl (which                alkyl can be substituted with alkyloxyimino),                alkoxycarbonyl, a group Ar which is (C₆-C₁₀) aryl or                (C₅-C₉) heteroaryl (wherein the heteroatom is one                oxygen, one sulfur or one nitrogen) or Ar-alkyl; and        -   R⁶ is independently hydrogen, hydroxyalkyl,            (C2-C6)alkanoylalkyl, alkyl, alkoxycarbonylalkyl, alkenyl,            carboxyalkyl (which alkyl can be substituted with            alkyloxyimino), alkoxycarbonyl, a group Ar which is            (C6-C 10) aryl or (C5-C9) heteroaryl (wherein the heteroatom            is one oxygen, one sulfur or one nitrogen) or Ar-alkyl;            wherein each group Ar can be substituted by one or more            halo, amino, alkyl, alkoxy, alkoxycarbonyl, sulfo, or            sulfoalkyl, groups, or a C₁-C₃ alkylenedioxy group, or a            pharmaceutically acceptable salt of said compounds, with the            proviso recited above. In this context,            “(C₂-C₆)alkanoylalkyl” identifies the carbon number for the            entire substituent.            Arteriosclerosis, Atherosclerosis, Stiff Vessel Disease,            Peripheral Vascular Disease, Coronary Stroke

Arteriosclerosis is a disease marked by thickening, hardening, and lossof elasticity in arterial walls, of which atherosclerosis is a sub-type.Arteriosclerosis in turn falls within the genus of stiff vesseldiseases. Without limitation to theory, it is believed that damage tothe blood vessels of these diseases is due to AGE-caused damage, eitherthrough protein cross-linking or the stimulation of bioactive agents, orboth. Accordingly, the agents are used to treat, prevent, reduce orameliorate stiff vessel disease, including arteriosclerosis andatherosclerosis. Peripheral vascular disease is an indication thatoverlaps with atherosclerosis but also covers disease which is believedto have a stronger inflammatory component. First agents are used totreat, prevent, reduce or ameliorate peripheral vascular disease.Coronary heart disease is a form of atherosclerosis of the coronaryarteries. First agents are used to treat, prevent, reduce or amelioratecoronary heart disease.

When the heart pumps blood into the vascular system, the ability of thearteries to expand helps to push blood through the body. When arteriesbecome stiff, as they do in the natural process of aging, the ability ofthe arteries to expand is diminished and also has consequences for theheart. The heart has to work harder to pump the blood into the stiffarteries, and eventually hypertrophies (enlarges in size) to accomplishthis. A hypertrophied heart is an inefficient pump, and is one of thedisorders that leads to congestive heart failure. One compound believedto work by a mechanism shared by the compounds of the invention showedan ability to reverse the stiffness of arteries in a Phase IIa clinicaltrial, as measured by the ratio of stroke volume (ml) to pulse pressure(mm Hg). The potential clinical benefit of this is to lessen the effortthat the heart must expend to push blood throughout the body. The effectis also believed to contribute to preventing hypertrophy and subsequentinefficiency of the heart, which inefficiency would contribute tocongestive heart failure.

Stroke is a cardiovascular disease that occurs when blood vesselssupplying blood (oxygen and nutrients) to the brain burst or areobstructed by a blood clot or other particle. Nerve cells in theaffected area of the brain die within minutes of oxygen deprivation andloss of nerve cell function is followed by loss of corresponding bodilyfunction. Of the four main types of stroke, two are caused by bloodclots or other particles. These two types are the most common forms ofstroke, accounting for about 70-80 percent of all strokes.

Blood clots usually form in arteries damaged by atherosclerosis. Whenplaque tears from the sheer forces of blood flowing over an uneven,rigid cap atop the plaque site, thrombotic processes become involved atthe “injury” site. As a result, clots can form. First agents are used toprevent, reduce or ameliorate the risk of stroke in patients who havesuffered previous strokes or have otherwise been identified as at risk.

First agents can also be used to treat, prevent, reduce or ameliorateperipheral vascular disease and periarticular rigidity.

Atherosclerosis is a disease that involves deposition of blood lipids inplaque in the arteries throughout the body. In coronary arteries,accumulation of plaque progressively leads to reduced coronary flow,with occlusion of the arteries causing focal death of cardiac tissue(myocardial infarction, heart attack). If the amount of tissue that diesis large enough, death ensues. In a Phase IIa trial, one compoundbelieved to work by a mechanism shared by the compounds of the inventionincreased the amount of circulating triglycerides (lipids). Consistentwith the known presence of AGEs in plaque, the result indicates that theagent had a lipid mobilizing effect on arterial plaque. Reducing localdeposits of plaque should eventually lessen the risk of myocardialinfarction and death due to heart attacks.

Rheumatoid Arthritis, Osteoarthritis, Bone Resorption

It is believed, without limitation to such theory, that reducing AGEaccumulation at the joints affected by rheumatoid arthritis orosteoarthritis reduces stimulation of the production of cytokinesinvolved in inflammatory processes of the disease. Treatment using theinvention is expected to treat, prevent, reduce or ameliorate rheumatoidarthritis or osteoarthritis. Similarly, it is believed that reducing AGEaccumulation at bone reduces stimulation of bone resorption.Accordingly, the invention is used to treat, prevent, reduce orameliorate osteoporosis, bone loss or brittle bone.

Dialysis

The agents can be administered as part of a dialysis exchange fluid,thereby preventing, limiting or ameliorating the damage to tissue causedby the sugars found in such exchange fluid. For example, agents areexpected to prevent, limit or ameliorate the stiffening and sclerosingof peritoneal tissue that occurs in peritoneal dialysis, as well asprevent, limit or ameliorate the formation of new blood vessels in theperitoneal membrane. In hemodialysis, agents are expected to prevent,limit or ameliorate the stiffening and sclerosing of red blood cells andvasculature resulting from exposure to the sugars exchanged into theblood during dialysis. Exchange fluids for peritoneal dialysis typicallycontain 10-45 g/L of reducing sugar, typically 25 g/L, which causes theformation of AGEs and consequent stiffening and degradation ofperitoneal tissue. Similarly, hemodialysis fluids typically contain upto about 2.7 g/L of reducing sugar, typically 1 to 1.8 g/L. Thus, theinvention provides methods by which the agents are provided in thesefluids and thereby prevent, limit or ameliorate the damage that wouldotherwise result. Alternatively, the invention provides methods wherebythe agents are administered by the methods described below to prevent,limit or ameliorate such damage from dialysis. In hemodialysis, theexchange fluid preferably contains 0.006-2.3 mg/L of an agent of theinvention, more preferably, 0.06 to 1.0 mg/L. In peritoneal dialysis,the exchange fluid preferably contains 0.01 to 24 mg/L of an agent ofthe invention, or preferably, 1.0 to 10 mg/L.

In one embodiment, preventing or ameliorating is effected with a secondagent, which is a compound of the aminoguanidine class as describedbelow. A preferred route of administration is inclusion in the dialysisfluids. In hemodialysis, the exchange fluid preferably contains 0.125 to2.5 mg/L of aminoguanidine, more preferably, 0.2 to 1.0 mg/L. Inperitoneal dialysis, the exchange fluid preferably contains 1.25 to 25mg/L of aminoguanidine, or preferably, 2.0 to 10 mg/L. In a preferredaspect of the invention, the agents are initially administered, andsubsequently second agents are used to moderate or limit damagethereafter.

Sickle Cell Anemia

It is believed, without limitation to such theory, that the agents actto prevent, reduce or ameliorate the restraint on blood flow caused bysickling. Again without limitation to theory, the mode of action isbelieved to be in reducing vascular as well as blood cell inelasticity.Accordingly, the agents are used to treat, prevent, reduce or amelioratesickle cell anemia.

End Stage Renal Disease, Diabetic Nephropathy

Diabetic Nephropathy is a complication of diabetes that evolves early,typically before clinical diagnosis of diabetes is made. The earliestclinical evidence of nephropathy is the appearance of low but abnormallevels (>30 mg/day or 20 μg/min) of albumin in the urine(microalbuminuria), followed by albuminuria (>300 mg/24 h or 200 μg/min)that develops over a period of 10-15 years. In patients with type 1diabetes, diabetic hypertension typically becomes manifest early on, bythe time that patients develop microalbuminuria. Once overt nephropathyoccurs, the glomerular filtration rate (GFR) falls over several yearsresulting in End Stage Renal Disease (ESRD) in 50% of type 1 diabeticindividuals within 10 years and in >75% of type 1 diabetics by 20 yearsof onset of overt nephropathy. Albuminuria (i.e., proteinuria) is amarker of greatly increased cardiovascular morbidity and mortality forpatients with either type 1 or type 2 diabetes.

Without limitation to theory, it is believed that damage to theglomeruli and blood vessels of the kidney is due to AGE-caused damage,either through protein cross-linking or the stimulation of bioactiveagents, or both. Accordingly, the agents are used to treat, prevent,reduce or ameliorate damage to kidney in patients at risk for ESRD. Theagents can also be used to treat, prevent, reduce or ameliorateglomerulosclerosis.

Hypertension, Isolated Systolic Hypertension

Cardiovascular risk correlates more closely with the systolic and thepulse pressure than with the diastolic pressure. In diabetic patients,the cardiovascular risk profile of diabetic patients is stronglycorrelated to duration of diabetes, glycemic control and blood pressure.Structural matrix proteins contribute to the function of vessels and theheart, and changes in the physical behavior of cardiovascular walls arebelieved to be important determinants of circulatory function. Inelderly individuals, the loss of compliance in the aorta leads toisolated systolic hypertension, which in turn expands the arterial walland thereby diminishes the dynamic range of elasticity. In vivo studiesin rodents, canines and in primates indicate potential utility of acompound believed to operate by the AGE-mediated mechanism insubstantially ameliorating vascular stiffening. For example, in a dogmodel for diabetes, lower end diastolic pressure and increased enddiastolic volume, indicators of ventricular elasticity, returned to avalue at about the mid-point between the disease impaired value and thevalue for control dogs. Treatment with the shared-mechanism compoundlead to a reduction in the mass of collagen in cardiovascular tissues.In situ hybridization studies demonstrate that the compound reduces theexpression of both Type IV collagen and TGFbeta.

Compared with that of a non-diabetic, the diabetic artery is smaller asit is stiffer. As in isolated systolic hypertension in which vesselsstiffen with age and lose the dynamic range of expansion under systole.First agents are used to treat, prevent, reduce or amelioratehypertension, including isolated systolic hypertension and diabetichypertension. Moreover, the same benefit is anticipated for the morerare hypertensive disorder, pulmonary hypertension. Pulmonaryhypertension is a rare blood vessel disorder of the lung in which thepressure in the pulmonary artery (the blood vessel that leads from theheart to the lungs) rises above normal levels and may become lifethreatening. The similarity in development of elevated blood pressure inthe pulmonary bed with the increase in systemic blood pressure indiabetic hypertension and in isolated systolic hypertension suggestssimilar mechanisms are involved.

Pulse pressure is the difference between systolic and diastolic bloodpressure. In a young human, systolic pressure is typically 120 mm Hg anddiastolic pressure is 80 mm Hg, resulting in a pulse pressure of 40 mmHg. With age, in many individuals pulse pressure increases, largely dueto the increase in systolic pressure that results from stiff vesseldisease. In individuals with pulse pressure greater than 60 mm Hg thereis an increased risk of death from cardiovascular morbidities. In aPhase Ia trial, one compound believed to work by a mechanism shared bythe compounds of the invention reduced pulse pressure in elderlypatients with pulse pressures greater than 60 mm Hg in a statisticallysignificant manner. This decrease in pulse pressure was believed to bedue primarily to the effect of the agent on lowering the systolic bloodpressure.

The agents of the invention are used to treat, prevent, reduce orameliorate reduced vascular compliance, elevated pulse pressure, andhypertension. Moreover, the agents are used to reduce pulse pressure,increase vascular compliance, or decrease the risk of death.

Heart Failure

Congestive Heart Failure (CHF) is a clinical syndrome that entailscardiac disease of the ventricle. Diastolic dysfunction is a subset ofheart failure in which the left ventricle stiffens with age. Thestiffening of the left ventricle that occurs in CHF and in diastolicdysfunction is believed to result from increased crosslinking ofcollagen fibers with age and/or fibrosis and related hypertrophy. Firstagents are used to treat, prevent, reduce or ameliorate heart failure.

Retinopathy

The effect of diabetes on the eye is called diabetic retinopathy andinvolves changes to the circulatory system of the retina. The earliestphase of the disease is known as background diabetic retinopathy whereinthe arteries in the retina become weakened and leak, forming small,dot-like hemorrhages. These leaking vessels often lead to swelling oredema in the retina and decreased vision. The next stage isproliferative diabetic retinopathy, in which circulation problems causeareas of the retina to become oxygen-deprived or ischemic. New vesselsdevelop as the circulatory system attempts to maintain adequate oxygenlevels within the retina. Unfortunately, these new vessels hemorrhageeasily. In the later phases of the disease, continued abnormal vesselgrowth and scar tissue may cause serious problems such as retinaldetachment and glaucoma. First agents are used to treat, prevent, reduceor ameliorate diabetic retinopathy. The agents can be administered bythe methods described below, including by topical administration to theeye. The agents can also be administered by intravitreal implant.

Cataracts, Other Damage to Lens Proteins

AGE-mediated crosslinking and/or fibrotic processes are believed tocontribute to cataract formation and formation of other damage to lensproteins. First agents are used to treat, prevent, reduce or amelioratecataracts or other damage to lens proteins.

Alzheimer's Disease

Considerable evidence exists implicating AGEs that form in theneurofibrillary tangles (tau protein) and senile plaques (beta-amyloidpeptide) in early neurotoxic processes of Alzheimer's disease. Insolublehuman tau protein is likely crosslinked. Glycation of insoluble tau fromAD patients and experimentally AGE-modified tau generate oxygen freeradicals, resulting in the activation of transcription via nuclearfactor-kappa B, and resulting in an increase in amyloid beta-proteinprecursor and release of amyloid beta-peptides. Thus, A.G.E.-modifiedtau may function as an initiator in a positive feedback loop involvingoxidative stress and cytokine gene expression. First agents are used totreat, prevent, reduce or ameliorate Alzheimer's disease.

Other Indications

For reasons analogous to those set forth above, the invention isbelieved to be useful in treating, preventing, reducing or amelioratingdiabetes or its associated adverse sequelae, and peripheral neuropathy.The agents, especially in topical form, increase elasticity and/orreduce wrinkles in skin. The agents further increase red blood celldeformability.

Combination Therapies

For all indications, agents can be administered concurrently or in acombined formulation with aminoguanidine or other agents of theaminoguanidine class, which are administered in effective amounts as isknown in the art. These agents are preferably administered separatelyfrom the other compounds described herein. These agents includecompounds of formula A

-   -   wherein R is an alkyl group, or a group of the formula        —N(R⁴)(R⁵) wherein R⁴ is hydrogen, and R⁵ is an alkyl group or a        hydroxyalkyl group; or R⁴ and R⁵ together with the nitrogen atom        are a heterocyclic group containing 4-6 carbon atoms and, in        addition to the nitrogen atom, 0-1 oxygen, nitrogen or sulfur        atoms; R¹ is hydrogen or an amino group; R² is hydrogen or an        amino group; R³ is hydrogen or an alkyl group, wherein R and R¹        cannot both be amino groups. Preferably at least one of R¹, R²,        and R³ is other than hydrogen. The compounds can be used as        their pharmaceutically acceptable acid addition salts, and        mixtures of such compounds. When aminoguanidine compounds are        administered, they can be administered by any route of        pharmaceutical administration including those discussed below        for other first agents.

The method of the invention is used to treat animals, preferablymammals, preferably humans.

In accordance with the present invention, methods for administeringpharmaceutical compositions containing compounds have been developed forthe treating the indications of the invention. These agents are eithersubstituted thiazole, oxazole, or imidazole agents as shown in theSummary section above.

As is noted in the formula for I, IA and III, the invention includesaromatic thiazole, oxazole, and imidazole analogs, as well as nonaromatic analogs thereof such as thiazoline, thiazolidine, oxazoline,oxazolidine, imidazoline, and imidazolidine analogs.

The alkyl, and alkenyl groups referred to above include both C1 to C6linear and branched alkyl and alkenyl groups, unless otherwise noted.Alkoxy groups include linear or branched C1 to C6 alkoxy groups, unlessotherwise noted. The size range for carbon-containing substituents thatby definition need a minimum of two carbons, or which need a minimumnumber of carbons for stability, will be recognized to start from theappropriate size. These groups are optionally substituted by one or morehalo, hydroxy, amino or lower alkylamino groups.

“Ar” (consistent with the rules governing aromaticity) refers to a C₆ orC₁₀ aryl, or a 5 or 6 membered heteroaryl ring. The heteroaryl ringcontains at least one and up to three atoms of N for the 6 memberedheteroaryl ring. The 5 membered heteroaryl ring contains; (1) from oneto three atoms of N, or (2) one atom of O or S and zero to two atoms ofN. Nonlimiting examples of heteroaryl groups include: pyrrolyl, furanyl,thienyl, pyridyl, oxazolyl, pyrazolyl, pyrimidinyl, and pyridazinyl.

“Ar” can be fused to either a benzene, pyridine, pyrimidine, pyridazine,or (1,2,3) triazine ring. As used herein, C₆ or C₁₀ aryl groups andheteroaryl containing five or six, or nine to ten ring members aremonocyclic or bicyclic.

In certain embodiments of the invention, the thiazoles, imidazoles, andoxazoles of the invention contain R^(a) and R^(b) substitutions thattogether with their ring carbons (the C4-C5 carbons of the thiazoles,imidazoles, and oxazoles) form a five to eight membered fusedheterocycle (i.e. a bicyclic heterocycle is formed). In theseembodiments the fused heterocycle is preferably not aromatic. Particularcompounds within these embodiments contain sulfur atoms in the fusedheterocycle (the ring fused to the thiazoles, imidazoles, and oxazoles).These sulfur atoms in these particular compounds can exist in variousoxidation states, as S(O)_(n), where n is 0,1, or 2.

In certain embodiments of the invention, thiazoles, imidazoles, andoxazoles of the invention contain R^(a) and R^(b) substitutions thattogether with their ring carbons (the C4-C5 carbons of the thiazoles,imidazoles, and oxazoles) form a C5 to C7 cycloalkyl ring having up totwo double bonds including the C4-C5 double bond. In other embodiments acycloalkyl ring is present when R^(e) is a C3 to C8 cycloalkyl ring. Thecycloalkyl groups can be substituted by one or more of the groupconsisting of alkyl-, alkoxycarbonyl-, amino-, aminocarbonyl-, carboxy-,fluoro-, or oxo-substituents. One of ordinary skill in the art willrecognize that where cycloalkyl groups contain double bonds, the sp²hybridized carbon atoms can contain only one substituent (which cannotbe amino- or oxo-). Sp³ hybridized carbon atoms in the cycloalkyl ringcan be geminally substituted with the exception that (1) two aminogroups and (2) one amino and one fluoro group can not be substituted onthe same sp³ hybridized carbon atom.

In certain embodiments of the invention, the thiazoles, imidazoles, andoxazoles of the invention contain R^(a) and R^(b) substitutions thattogether with their ring carbons (the C4-C5 carbons of the thiazoles,imidazoles, and oxazoles) form a five or six membered heteroaryl ring(i.e, a bicyclic aromatic heterocycle is formed). A preferred bicyclicaromatic heterocycle of the invention is a purine analog [J is N-R^(d)and R^(a) and R^(b) together with their ring carbons (the C4 and C5 ofthe imidazole ring) form a pyrimidine ring].

Aryl, Ar, or Ar^(φ) can be substituted with, in addition to anysubstitutions specifically noted one or more substituents selected fromthe group of acylamino, acyloxyalkyl, alkanoyl, alkanoylalkyl, alkenyl,alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylamino,(C1-C3)alkylenedioxy, alkylsulfonyl [alkylSO₂-], alkylsulfinyl[alkylSO-], ω-alkylenesulfonic acid [—(CH₂)_(n)SO₃H where n=1 to 6],alkylthio, allyl, amino, ArC(O)—, ArC(O)NH—, carboxy, carboxyalkyl,cycloalkyl, dialkylamino, halo, trifluoromethyl, hydroxy,(C2-C6)hydroxyalkyl, mercapto, nitro, ArO—, Ar—, Ar-alkyl-, sulfamoyl,sulfonic acid, morpholin-4-yl, thiomorpholin-4-yl, piperidin-1-yl,1-pyrrolidinyl, 4-[C₆ or C₁₀]arylpiperidin-1-yl and 4-[C₆ orC₁₀]arylpiperazin-1-yl.

Heterocycles, except those of Ar and Ar^(φ), can be substituted with inaddition to any substitutions specifically noted one or moresubstituents selected from acylamino, alkanoyl, alkoxy, alkoxycarbonyl,alkoxycarbonylalkyl, alkyl, (C1 to C3)alkylenedioxy, alkylamino,alkylsulfonyl, alkylsulfinyl, alkylthio, amino, ArC(O)—, ArO—, Ar—,Ar-alkyl, carboxy, dialkylamino, fluoro, fluoroalkyl, difluoroalkyl,hydroxy, mercapto, oxo, sulfamoyl, trifluoromethyl, 4-[C₆ orC₁₀]arylpiperidin-1-yl and 4-[C₆ or C₁₀]arylpiperazin-1-yl, whereinmultiple substituents are located on different atoms of the heterocyclicring, with the proviso that alkyl, alkoxycarbonyl, and fluorosubstituents can be substituted on the same carbon atom of theheterocyclic ring. Heterocycles can be substituted with one or moresubstituents.

The halo atoms can be fluoro, chloro, bromo or iodo. Chloro and fluoroare preferred for aryl substitutions.

In certain embodiments, such compounds are not

-   -   (1) 5-methylthiazole,    -   (2) benzothiazole, or    -   (3) 2,6-diamino-benzothiazole.

The method can comprise administering an amount effective therefor ofone or more compounds of the following formula:

The method can also comprise administering an amount effective thereforof one or more compounds of the following formula:

The method can also comprise administering an amount effective thereforof one or more compounds of formula I, wherein each Ar or cycloalkylgroup is substituted with up to two substituents.

In some embodiments of this invention, the compounds of formula I, IAand III can form biologically and pharmaceutically acceptable salts.Useful salt forms include the halides, particularly the bromide,chloride, tosylate, methanesulfonate, brosylate, fumarate, maleate,succinate, acetate, mesitylenesulfonate and the like. Other relatedsalts can be formed using similarly non-toxic, biologically orpharmaceutically acceptable anions.

Representative, non-limiting examples of compounds of the presentinvention are:

-   Thiazole-   4,5-Dimethylthiazole-   4-Methylthiazole-   5-Methylthiazole-   4-Methyl-5-(2-hydroxyethyl)thiazole-   4-Methyl-5-vinylthiazole-   Benzothiazole-   2-Aminobenzothiazole-   2-Amino-4-chlorobenzothiazole-   2-Amino-6-chlorobenzothiazole-   2,6-Diamino-benzothiazole-   2-Aminothiazole-   2,4,5-Trimethylthiazole-   2-Amino-5-methylthiazole-   2-Amino-4-methylthiazole-   2-Acetylthiazole-   2-Ethyl-4-methylthiazole-   Ethyl 2-(Formylamino)-4-thiazoleacetate-   2-(Formylamino)-alpha-(methoxyimino)-4-thiazoleacetic acid-   2-Amino-4-phenylthiazole hydrochloride monohydrate-   2-Isobutylthiazole-   2-Methyl-2-thiazoline-   2-Methyl-2-oxazoline-   2-Oxazolidone-   2-Amino-4-thiazoleacetic acid-   1-(Thiazolyl)-3-phenyl-urea-   1-(Thiazolidinyl)-3-(4-fluorophenyl)-urea-   (4-fluorophenyl)thiazolin-2-ylamine-   2-(4,6-dimethylpyrimidin-2-ylthio)-N-(1,3-thiazol-2′yl)acetamide,    also known as    N-(Thiazolyl)-2-(4,6-dimethyl-pyrimidin-2-yl-thio)-acetamide-   2-(4-propylphenoxy)-N-(thiazol-2-yl)acetamide-   2-furyl-N-[4-(6-methylbenzothiazol-2-yl)phenyl]carboxamide-   2-(3,5-Dimethylphenoxy)-N-thiazol-2-yl)acetamide-   5,5-Dimethyl-2-(2-naphthylamino)-4,5,6-trihydrobenzothiazol-7-one-   Imidazole-   1-Methylimidazole-   1-Ethylimidazole-   1-Butylimidazole-   1-Vinylimidazole-   1-Allylimidazole-   1-(Trimethylsilyl) imidazole-   1-(3-Aminopropyl) imidazole-   1-Benzyl imidazole-   1-Phenyl imidazole-   1,5-Dicyclohexyl imidazole-   1-(p-Toluenesulfonyl) imidazole-   N-Benzoyl-imidazole-   4-Methyl-imidazole-   4′-(Imidazol-1-yl)-acetophenone-   4-(Imidazol-1-yl)-phenol-   1-(4-Methoxyphenyl)-1H-imidazole-   Methyl-4-(1H-imidazol-1 yl)benzoate-   1-Methylbenzimidazole-   2-(3,5-dimethylphenoxy)-N-(4-methyl(1,3-thiazol-2-yl))acetamide-   2-(3,5-dimethylphenoxy)-N-(5-methyl(1,3-thiazol-2-yl))acetamide-   N-(4,5-dimethyl(1,3-thiazol-2-yl))-2-(3,5-dimethylphenoxy)acetamide-   2-(3,5-dimethylphenoxy)-N-[5-(2-hydroxyethyl)-4-methyl(1,3-thiazol-2-yl)]acetamide-   2-(3,5-dimethylphenoxy)-N-(5-chloro(1,3-thiazol-2-yl))acetamide-   N-benzothiazol-2-yl-2-(3,5-dimethylphenoxy)acetamide-   2-(3,5-dimethylphenoxy)-N-(5-bromo(1,3-thiazol-2-yl))acetamide-   2-(3,5-dimethylphenoxy)-N-(4-phenyl(1,3-thiazol-2-yl))acetamide-   ethyl    2-[2-(3,5-dimethylphenoxy)acetylamino]-4-phenyl-1,3-thiazole-5-carboxylate-   2-(3,5-dimethylphenoxy)-N-(5-nitro(1,3-thiazol-2-yl))acetamide-   2-(3,5-dimethylphenoxy)-N-(6-nitrobenzothiazol-2-yl)acetamide-   ethyl    2-[2-(3,5-dimethylphenoxy)acetylamino]-1,3-thiazole-4-carboxylate-   2-(3,5-dimethylphenoxy)-N-(1-methylimidazol-2-yl)acetamide-   2-(3,5-dimethylphenoxy)-N-(1-methylbenzimidazol-2-yl)acetamide-   2-(3,5-dimethylphenoxy)-N-[1-benzylbenzimidazol-2-yl]acetamide-   2-(3,5-dimethylphenoxy)-N-(5-chlorobenzoxazol-2-yl)acetamide    as well as other biologically and pharmaceutically acceptable salts    thereof.

Certain of the compounds of the invention are novel compounds whichrepresent a further embodiment of the present invention. These compoundsare represented, for example, by the compounds of formula I, IA or IIIwhere R^(c) or R³ is —NHC(O)(CH₂)_(n)-D-R^(e)R^(f) or—NHC(O)(CH₂)_(n)—Y—R⁵R⁶. In one embodiment, these are compounds wheren=1. In another embodiment, these are compounds where Y or D is oxygenor sulfur. In another embodiment, preferably where Y or D is oxygen orsulfur,

-   -   (a) Re is        -   (1)Ar,        -   (2) a group of the formula            -   wherein E is sulfur, oxygen, or N—R^(i), and R^(g),                R^(h) and R^(i) are independently the same as R^(a),                R^(b) and R^(d), respectively,        -   (3) a C₃-C₈ cycloalkyl ring having up to one double bond            with the proviso that the carbon linking the cyloalkyl ring            to D is saturated, which cycloalkyl ring can be substituted            by one or more alkyl-, alkoxycarbonyl-, amino-,            aminocarbonyl-, carboxy-, fluoro-, or oxo-substituents; or        -   (4) a 5- or 6-membered heteroaryl ring containing at least            one and up to three atoms of N for the 6-membered heteroaryl            rings and from one to three atoms of N or one atom of O or S            and zero to two atoms of N for the 5-membered heteroaryl            rings;            Or,    -   wherein R⁵ is        -   (i) Ar,        -   (ii) a group of the formula            -   wherein R⁷, R⁸ and R⁹ are independently the same as R¹,                R² and R⁴, Z is sulfur or nitrogen, R⁹ is present only                when Z is nitrogen;        -   (iii) a C₃-C₈ cycloalkyl or cycloalkenyl ring having up to            one double bond, which aliphatic ring can be substituted by            one or more amino, halo, alkyl, sulfo, sulfoalkyl, carboxy,            carboxyalkyl, or oxo groups; or        -   (iv) a 3 to 8-membered heterocyclic ring wherein the            heteroatom is one oxygen, one sulfur or one nitrogen, which            heterocyclic ring can be substituted by one or more amino,            halo, alkyl, sulfo, sulfoalkyl, carboxy, carboxyalkyl, or            oxo groups.            The above compounds where R^(c) or R³ is            —NHC(O)(CH₂)_(n)-D-R^(e)R^(f) or —NHC(O)(CH₂)_(n)—Y—R⁵R⁶ are            those wherein at least one of R^(a) and R^(b), or R¹ and R²            is other than hydrogen.

In one embodiment, the compound is according to Formula I or IA andR^(c) is dialkylamino(C₁-C₅)alkyl. In this embodiment, preferably, J issulfur.

Useful intermediates include a compound consistent with Formula I or IA,where R_(c) is ω-halo(C₂-C₅)alkyl. In this embodiment, preferably, J issulfur.

Further provided are compounds of formula I or IA,

-   -   wherein:    -   a. J is sulfur;    -   b. R^(a) is hydroxyalkyl or alkyl omega-substituted with a        tertiary amine which is dialkyl amine or (i) incorporated into a        5- or 6-membered heteroaryl ring, wherein the 6-membered        heteroaryl ring contains one to three atoms of N, and the        5-membered heteroaryl ring contains from one to three atoms of N        or one atom of O or S and one to two atoms of N or (ii)        incorporated into a 5- or 6-membered non-aromatic heterocyclic        ring having one to two ring nitrogens; and    -   c. R^(b) and R^(c) are alkyl. These compounds can be used in the        methods of the invention.

Also provided are compounds of formula I or IA,

-   -   wherein:    -   a. J is sulfur;    -   b. the carbon 2 to nitrogen bond is a double bond;    -   c. the bond between carbons 4 and 5 is a double bond;    -   d. R^(a) and R^(b) are independently selected from hydrogen,        acylamino, alkanoyl, alkanoylalkyl, alkoxy, alkoxycarbonyl,        alkoxycarbonylalkyl, alkyl, (C2-C6)hydroxyalkyl, nitro,        trifluoromethyl, Ar {wherein, Ar is C₆ or C₁₀ aryl}, or        Ar-alkyl; and    -   c. R^(c) is alkyl omega-substituted with a tertiary amine which        is dialkyl amine or (i) incorporated into a 5- or 6-membered        heteroaryl ring, wherein the 6-membered heteroaryl ring contains        one to three atoms of N, and the 5-membered heteroaryl ring        contains from one to three atoms of N or one atom of O or S and        one to two atoms of N or (ii) incorporated into a 5- or        6-membered non-aromatic heterocyclic ring having one to two ring        nitrogens,    -   wherein aryl can be substituted with one or more substituents        selected from the group of acylamino, acyloxyalkyl, alkanoyl,        alkanoylalkyl, alkenyl, alkoxy, alkoxycarbonyl,        alkoxycarbonylalkyl, alkyl, (C1-C3)alkylenedioxy, alkylthio,        allyl, carboxyalkyl, cycloalkyl, dialkylamino, halo,        trifluoromethyl, hydroxy, (C₂-C₆)hydroxyalkyl, mercapto, nitro,        ArO—, Ar—, or Ar-alkyl-.        These compounds can be used in the methods of the invention.

Further provided are compounds of formula I or IA,

-   -   wherein:    -   a. J is sulfur;    -   b. the carbon 2 to nitrogen bond is a double bond;    -   c. the bond between carbons 4 and 5 is a double bond;    -   d. R^(a) and R^(b) are independently selected from hydrogen,        acylamino, alkanoyl, alkanoylalkyl, alkoxy, alkoxycarbonyl,        alkoxycarbonylalkyl, alkyl, (C2-C6)hydroxyalkyl, nitro,        trifluoromethyl, Ar {wherein, Ar is C₆ or C₁₀ aryl}, or        Ar-alkyl;    -   c. R^(c) is (C₂-C₅)alkyl omega-substituted with halo,    -   wherein aryl can be substituted with one or more substituents        selected from the group of acylamino, acyloxyalkyl, alkanoyl,        alkanoylalkyl, alkenyl, alkoxy, alkoxycarbonyl,        alkoxycarbonylalkyl, alkyl, (C1-C3)alkylenedioxy, alkylthio,        allyl, carboxyalkyl, cycloalkyl, dialkylamino, halo,        trifluoromethyl, hydroxy, (C2-C6)hydroxyalkyl, mercapto, nitro,        ArO—, Ar—, or Ar-alkyl-.

The compounds of the invention are capable of inhibiting the formationof advanced glycosylation endproducts on target molecules, including,for instance, proteins, as well as being capable of breaking orreversing already formed advanced glycosylation endproducts on suchproteins. The cross-linking of protein by formation of advancedglycosylation endproducts contributes to the entrapment of otherproteins and results in the development in vivo of conditions such asreduced elasticity and wrinkling of the skin, certain kidney diseases,atherosclerosis, osteoarthritis and the like. Similarly, plant materialthat undergoes nonenzymatic browning deteriorates and, in the case offoodstuffs, become spoiled or toughened and, consequently, inedible,unpalatable or non-nutritious. Thus, the compounds employed inaccordance with this invention inhibit this late-stage Maillard effectand intervene in the deleterious changes described above, and reduce thelevel of the advanced glycosylation endproducts already present in theprotein material.

A rationale of the present invention is to use agents which block, aswell as reverse, the post-glycosylation step, e.g., the formation offluorescent chromophores and cross-links, the presence of which isassociated with, and leads to adverse sequelae of diabetes and aging. Anideal agent would prevent the formation of such chromophores and ofcross-links between protein strands and trapping of proteins onto otherproteins, such as occurs in arteries and in the kidney, and reverse thelevel of such cross-link formation already present.

The chemical nature of the early glycosylation products with which thecompounds of the present invention are believed to react can vary.Accordingly the term “early glycosylation product(s)” as used herein isintended to include any and all such variations within its scope. Forexample, early glycosylation products with carbonyl moieties that areinvolved in the formation of advanced glycosylation endproducts, andthat can be blocked by reaction with the compounds of the presentinvention, have been postulated. In one embodiment, the earlyglycosylation product can comprise the reactive carbonyl moieties ofAmadori products or their further condensation, dehydration and/orrearrangement products, which can condense to form advancedglycosylation endproducts. In another scenario, reactive carbonylcompounds, containing one or more carbonyl moieties (such asglycolaldehyde, glyceraldehyde or 3-deoxyglucosone) can form from thecleavage of Amadori or other early glycosylation endproducts, and bysubsequent reactions with an amine or Amadori product, can form carbonylcontaining advanced glycosylation products such asalkylformyl-glycosylpyrroles.

While not wishing to be bound by any particular theory as to themechanism by which the compounds of the instant invention reversealready formed advanced glycosylation endproducts, studies have beenstructured to elucidate a possible mechanism. Earlier studies examiningthe fate of the Amadori product (AP) in vivo have identified one likelyroute that could lead to the formation of covalent, glucose-derivedprotein crosslinks. This pathway proceeds by dehydration of the AP viasuccessive beta-eliminations as shown in the Scheme A of U.S. Pat. No.5,853,703. Thus, loss of the 4-hydroxyl of the AP (1) gives a1,4-dideoxy-1-alkylamino-2,3-hexodiulose (AP-dione) (2). An AP-dionewith the structure of an amino-1,4-dideoxyosone has been isolated bytrapping model APs with the AGE-inhibitor aminoguanidine. Subsequentelimination of the 5-hydroxyl gives a1,4,5-trideoxy-1-alkylamino-2,3-hexulos-4-ene (AP-ene-dione) (3), whichhas been isolated as a triacetyl derivative of its 1,2-enol form.Amadori-diones, particularly the AP-ene-dione, would be expected to behighly reactive toward protein crosslinking reactions by serving astargets for the addition of the amine (Lys, His)-, or sulfhydryl(Cys)-based nucleophiles that exist in proteins, thereby producingstable crosslinks of the form (4). Note that the linear AP-ene-dione of(3) and the stable cross-link of (4) can cyclize to form either 5- or6-member lactol rings. See, the scheme shown in U.S. Pat. No. 5,853,703.

The possibility that a major pathway of glucose-derived crosslinkformation proceeds through an AP-ene-dione intermediate was investigatedby experiments designed to test the occurrence of this pathway in vivoas well as to effect the specific cleavage of the resultantα-dicarbonyl-based protein crosslinks. Without being limited to theory,at least some of the compounds of the invention are believed to act as“bidentate” nucleophiles, particularly designed to effect acarbon-carbon breaking reaction between the two carbonyls of thecrosslink, in a similar manner to Scheme B of U.S. Pat. No. 5,853,703.

Therapeutic implications of the present invention relate to the arrest,and to some extent, the reversal of the aging process which has, asindicated earlier, been identified and exemplified in the aging of keyproteins by advanced glycosylation and cross-linking. Thus, bodyproteins, and particularly structural body proteins, such as collagen,elastin, lens proteins, nerve proteins, kidney glomerular basementmembranes and other extravascular matrix components would all benefit intheir longevity and operation from the practice of the presentinvention. The present invention thus reduces the incidence ofpathologies involving the entrapment of proteins by cross-linked targetproteins, such as retinopathy, cataracts, diabetic kidney disease,glomerulosclerosis, peripheral vascular disease, arteriosclerosisobliterans, peripheral neuropathy, stroke, hypertension,atherosclerosis, osteoarthritis, periarticular rigidity, loss ofelasticity and wrinkling of skin, stiffening of joints,glomerulonephritis and the like. Likewise, all of these conditions arein evidence and tend to occur at an accelerated rate in patientsafflicted with diabetes mellitus as a consequence of this hyperglycemia.Thus, the present therapeutic method is relevant to treatment of theseand related conditions in patients either of advanced age or thosesuffering from one of the mentioned pathologies.

Protein cross-linking through advanced glycosylation product formationcan decrease solubility of structural proteins such as collagen invessel walls and can also trap serum proteins, such as lipoproteins tothe collagen. Also, this can result in increased permeability of theendothelium and consequently covalent trapping of extravasated plasmaproteins in subendothelial matrix, and reduction in susceptibility ofboth plasma and matrix proteins to physiologic degradation by enzymes.For these reasons, the progressive occlusion of diabetic vessels inducedby chronic hyperglycemia is believed to result from excessive formationof glucose-derived cross-links. Such diabetic microvascular changes andmicrovascular occlusion can be effectively prevented and reversed bychemical inhibition and reversal of the advanced glycosylation productformation utilizing a composition and the methods of the presentinvention.

Molecular cross-linking through advanced glycosylation product formationcan decrease solubility of structural proteins such as collagen invessel walls and can also trap serum proteins, such as lipoproteins tothe collagen. Also, this can result in increased permeability of theendothelium and consequently covalent trapping of extravasated plasmaproteins in subendothelial matrix, and reduction in susceptibility ofboth plasma and matrix proteins to physiologic degradation by enzymes.For these reasons, the progressive occlusion of diabetic vessels inducedby chronic hyperglycemia has been hypothesized to result from excessiveformation of sugar-derived and particularly, glucose-derivedcross-links. Such diabetic microvascular changes and microvascularocclusion can be effectively prevented and reversed by chemicalinhibition and reversal of the advanced glycosylation product formationutilizing a composition and the methods of the present invention.

Studies indicate that the development of chronic diabetic damage intarget organs is primarily linked to hyperglycemia so that tightmetabolic control would delay or even prevent end-organ damage. SeeNicholls et al., Lab. Invest., 60, No. 4, p. 486 (1989), which discussesthe effects of islet isografting and aminoguanidine in murine diabeticnephropathy. These studies further evidence that aminoguanidinediminishes aortic wall protein cross-linking in diabetic rats andconfirm earlier studies by Brownlee et al., Science, 232:1629-1632(1986) to this additional target organ of complication of diabetes.Also, an additional study showed the reduction of immunoglobulintrapping in the kidney by aminoguanidine (Brownlee et al., Diabetes,(1):42A (1986)).

Further evidence in the streptozotocin-diabetic rat model thataminoguanidine administration intervenes in the development of diabeticnephropathy was presented by Brownlee et al., Science, 232:1629-1632(1986), with regard to morphologic changes in the kidney which arehallmarks of diabetic renal disease. These investigators reported thatthe increased glomerular basement membrane thickness, a major structuralabnormality characteristic of diabetic renal disease, was prevented withaminoguanidine.

Taken together, these data strongly suggest that inhibition and reversalof the formation of advanced glycosylation endproducts (AGEs), by theteaching of the present invention, can prevent, as well as to someextent reverse late, as well as early, structural lesions due todiabetes, as well as changes during aging caused by the formation ofAGEs.

Diabetes-induced changes in the deformability of red blood cells,leading to more rigid cell membranes, is another manifestation ofcross-linking and aminoguanidine has been shown to prevent it in vivo.In such studies, New Zealand White rabbits, with induced, long-termdiabetes are used to study the effects of a test compound on red bloodcell (RBC) deformability (df). The test compound is administered at arate of 100 mg/kg by oral gavage (tube delivery to stomach) to diabeticrabbits.

A further consequence of diabetes is the hyperglycemia-induced matrixbone differentiation resulting in decreased bone formation usuallyassociated with chronic diabetes. In animal models, diabetes reducesmatrix-induced bone differentiation by 70%.

In the instance where the compositions of the present invention areutilized for in vivo or therapeutic purposes, it can be noted that thecompounds or agents used therein are biocompatible. Pharmaceuticalcompositions can be prepared with a therapeutically effective quantityof the agents or compounds of the present invention and can include apharmaceutically acceptable carrier, selected from known materialsutilized for this purpose. Such compositions can be prepared in avariety of forms, depending on the method of administration. Also,various pharmaceutically acceptable addition salts of the compounds ofthe invention can be utilized.

Where one or more compounds of formula I are administered to decreaseintraocular pressure, at least one compound of formula I administered ineffective amount is not a thiazole substituted on a ring carbon withsulfonamide (the amide of which can be substituted) that has carbonicanhydrase inhibiting activity. Of course, the composition can include aneffective amount of such an agent, as well as a carbonicanhydrase-inhibiting effective amount of another agent, including one ofthose distinguished above.

Compounds of the formula I can be conveniently prepared by chemicalsyntheses well-known in the art. Certain of the compounds are well-knownand readily available from chemical supply houses or can be prepared bysynthetic methods specifically published therefor. For instance,4,5-Dimethylthiazole, 4-Methylthiazole, 5-Methylthiazole,4-Methyl-5-thiazoleethanol, 4-Methyl-5-vinylthiazole, Benzothiazole,2-Aminobenzothiazole, 2-Amino-4-chlorobenzothiazole,2-Amino-6-chlorobenzothiazole, 2-Aminothiazole, 2,4,5-Trimethylthiazole,2-Amino-5-methylthiazole, 2-Amino-4-methylthiazole, 2-Acetylthiazole,2-Ethyl-4-methylthiazole, Ethyl 2-(Formylamino)-4-thiazoleacetate,2-(Formylamino)-alpha-(methoxyimino)-4-thiazoleacetic acid,2-amino-4-phenylthiazole hydrochloride monohydrate, 2-Isobutylthiazole,2-Methyl-2-thiazoline, 2-Methyl-2-oxazoline, 2-Oxazolidone,Thiomorpholine, 2-Amino-4-thiazoleacetic acid, Imidazole,1-Methylimidazole, 1-Butylimidazole, 1-Vinylimidazole, 1-Allylimidazole,1-(Trimethylsilyl) imidazole, 1-(3-Aminopropyl) imidazole, 1-Benzylimidazole, 1-Phenyl imidazole, 1,5-Dicyclohexyl imidazole,1-(p-Toluenesulfonyl) imidazole, N-Benzoyl-imidazole,4-Methyl-imidazole, 4′-(Imidazol-1-yl)-acetophenone,4-(Imidazol-1-yl)-phenol, 1-(4-Methoxyphenyl)-1H-imidazol and1-Methylbenzimidazole can be obtained from Sigma (St. Louis, Mo.),Aldrich (Milwakee, Wis.) or Fluka (Milwaukee, Wis.) (all divisions ofSigma-Aldrich Co.). 1-ethylimidazole can be obtained from TCI America(Portland, Oreg.). N-(Thiazolidinyl)-4-fluoroaniline,N-(Thiazolyl)-2-(4,6-dimethyl-pyrimidin-2-yl-thio)-acetamide,N-(Thiazolyl)-2-(4-propylphenoxy)-acetamide,2-[4-(N-Furoyl)aminophenyl]-6-methylbenzothiazole,N-(Thiazolyl)-2-(3,5-dimethylphenoxy-acetamide and2-[(N-(2-Napthalenyl)amino]-[2,3:5,4]-(5,5-dimethyl-cyclohexanonyl)]thiazolecan be purchased from MDD, Inc. (Acton, Ontario), a successor to OrtechCorporation.

In one synthetic process to prepare compounds of the general formula I,a thiazole is reacted with an alkyl or acyl halide in the presence ofbase such as triethylamine, to produce the corresponding alkyl or acylderivative at the 2 carbon. See, Medici et al., J. Org. Chem. 49:590-596, 1984. In some cases, a chromatographic step is applied toseparate additions at the 2 and 3 positions of the thiazole ring.

In another synthesis of compounds of the formula I wherein R^(c) isamino, nitro-containing analogs of compounds of the invention orprecursors thereof are catalytically hydrogenated to the correspondingamino compounds.

2-Amino thiazole compounds wherein (R^(c) is amino) can also besynthesized by reacting thiourea (which can be substituted on at leastone amine) with an alpha-halo ketone using the method described in Vogel's Textbook of Practical Organic Chemistry, 5^(th) Edition, John Wiley &Sons, New York, p. 1153. Such a reaction is exemplified by a synthesisof 2-amino-4-phenylthiazole:

Thiazoles substituted on the ring nitrogen can be prepared by alkylationor acylation with appropriate acyl or alkyl halides.

N-aryl thiazoles and imidazoles can be prepared using appropriatearomatic nucleophilic displacement reactions. For example, fluoro phenylcompounds such as 4-fluorobenzoic acid methyl ester can be used tosubstitute the N¹ nitrogen of imidazole to makemethyl-4-(1H-imidazol-1-yl)benzoate. See, Morgan et al., J. Med. Chem.33: 1091-1097, 1990.

Amino functions of 2-aminoimidazoles or 2-aminothiazoles can be acylatedby dehydration or other methods known in the art.

Substituted oxazoles can be prepared by methods known in the art. Forinstance, 2-unsubstituted oxazoles can be formed by condensation offormamide with either α-hydroxy or α-haloketones intermediates (H.Bredereck, R. Gommper, H. G. v. Shuh and G. Theilig, in Newer Methods ofPreparative Organic Chemistry, Vol. III, ed. W. Foerst, Academic press,New York, 1964, p. 241). The intermediates can cyclize under acidconditions to form the oxazole ring (Scheme 2). In addition,2,4-disubstituted oxazoles can be prepared from α-haloketones and amidesat higher temperatures using the same method.

Oxazoles can be prepared by cyclization reactions of isonitriles (vanLeusen, A. M. Lect. Heterocycl. Chem. 1980, 5, S111; Walborsky, H. M.;Periasamy, M. P. in The Chemistry of Functional Groups, suppl. C, Patai,S.; Rappoport, Z., Eds; Wiley-Interscience, 1983, p. 835; Hoppe, D.Angew. Chem. Int. Edn. Engl., 1974, 13, 789; Schollkopf, U. Angew. Chem.Int. Ed. Engl., 1977, 16, 339). For example, as shown below in Scheme 3,tosylmethyl isocyanide can be deprotonated by a base and reacted with asuitable electrophile (e.g. an aldehyde). The intermediate can cyclizeand aromatize to provide the desired oxazole analog. Other methods forpreparing oxazoles include 1,5-dipolar cyclization of acylated nitrileylides (Taylor E. C.; Turchi, I. J. Chem. Rev., 1979, 79, 181; Huisgen,R. Angew. Chem. Int. Edn. Engl. 1980, 19, 947)

2-Amino-substituted oxazoles (i.e. R^(c)═NH₂) can be prepared by twogeneral methods. Urea can be condensed with α-bromo ketones to yield2-aminooxazoles that can be substituted at the 4 and 5 positions (Scheme4). Alternatively, another route to 2-aminooxazoles from acyclicprecursors is the base catalyzed reaction of cyanamide with α-hydroxyketones (Scheme 5). 2-Aminooxazoles of the invention can also beprepared from the nucleophilic displacement of amines with2-chlorooxazole, for example, for compounds of the invention whereinR^(c) is ArNH— (Gompper, R.; Effenberger, F. Chem. Ber., 1959, 92,1928).

Compounds of the invention, wherein R^(c) is arylcarbonyl can besynthesized by acylation of the amino moiety of 2-aminooxazoles with,for example, with anhydrides to yield 2-acylaminooxazoles. In addition,2-aminooxazoles can be acylated, for instance, with chloroaceticanhydride to yield an α-chloro carboxamide. The α-chloro carboxamide canserve as a suitable alkylating reagent that can be treated with, forexample, phenols, arylamines and alkylamines to prepare compounds of theinvention. An oxazole of the invention wherein Rc is Ar-oxycarbonylaminois shown in Scheme 6.

Oxazoles of the invention with Rc is aminocarbonylamino (ureido) oraminothiocarbonylamino (thioureido) can be prepared from 2-aminooxazoles(Scheme 7). 2-Aminooxazoles can be treated with isocyanates andisothiocyanates to yield 2-ureido and 2-thioureido oxazoles,respectively (Crank, G.; Foulis, J. J. Med. Chem., 1971, 14, 1075:Crank, G. Neville, M.; Ryden, R. J. Med. Chem., 1974, 16, 1402).

2-Aminooxazoles can be hydrogenated using palladium catalysts to yield2-aminooxazolines (Scheme 8) (Tanaka, C.; Kuriyama, S. Yakugaku Zasshi1979, 99, 78).

Benzoxazole intermediates substituted at the 2 position can be preparedfrom 2-aminophenols by acylation with, for example, an acid chloride andcyclization (Scheme 9).

Compounds of the general formula I wherin R^(a) is hydroxymethyl-,aminomethyl-, alkylaminomethyl, or dialkylaminomethyl- can be preparedfrom a halomethyl intermediate. In addition cyclic amines such aspiperidines, piperazines, and pyrrolidines substituted on a methyl group(i.e., for R^(a)) could also be prepared using the halomethylintermediate. Compounds of the invention where is 1-imidazolylmethyl-can also be prepared using the same intermediate. A suitable halomethylintermediate is exemplified in Scheme 10. Those of ordinary skill in theart will note while the intermediate in Scheme 10 is prepared using athiazole, other substituted thiazoles as well as oxazoles and imidazolescould be prepared analogously.

The halomethyl group can be hydrolyzed with, for example, using silvernitrate in water (Scheme 11). Alkylations with amines, including cyclicamines from the same intermediate, are also exemplified.

Compounds of the invention where R^(c) is hydroxymethyl-, amino (orsubstituted amino) methyl-, cyclic aminomethyl, or N-imidazol-ylmethyl-can be prepared in this manner. For example, a 2-hydroxymethyl thiazolecan be chlorinated with for example, thionyl chloride, phosphoruspentachloride, or phosphorus oxychloride to give a chloromethylintermediate that is a suitable for preparing the above mentionedcompounds (Scheme 12). Methods to prepare the compounds wherein R^(c) ishydroxymethyl and aminomethyl from the chloromethyl intermediate areanalogous to those methods illustrated in Scheme 11.

Compounds of the invention wherein R^(c) is hydroxyethyl-, amino(orsubstituted amino)ethyl-, cyclic aminoethyl, or N-imidazol-ylethyl- canbe prepared from a chloroethyl intermediate (Scheme 13). For instance, a2-hydroxyethyl thiazole intermediate can be prepared from metalation ofa thiazole (or by halogen-metal exchange from a 2-bromothiazole)followed by reaction with ethylene oxide. The resulting2-hydroxyethylthiazole can be converted to a chloroethylthiazole using achlorinating agent, such as thionyl chloride. Methods to prepare thecompounds wherein R^(c) is hydroxyethyl and aminoethyl from thechloroethyl intermediate are analogous to those methods illustrated inScheme 11.

Compounds that can be prepared using the methods depicted in Schemes10-13 include (2,5-dimethyl-1,3-thiazol-4-yl)methan-1-ol;[(2,5-dimethyl(1,3-thiazol-4-yl))methyl]dimethylamine;4-(imidazolylmethyl)-2,5-dimethyl-1,3-thiazole;2-(imidazolylmethyl)-1,3-thiazole;trimethyl(1,3-thiazol-2-ylmethyl)amine;2-(2-imidazolylethyl)-1,3-thiazole;dimethyl(2-(1,3-thiazol-2-yl)ethyl)amine; and2-(2-chloroethyl)-1,3-thiazole.

To treat the indications of the invention, an effective amount of apharmaceutical compound will be recognized by clinicians but includes anamount effective to treat, reduce, ameliorate, eliminate or prevent oneor more symptoms of the disease sought to be treated or the conditionsought to be avoided or treated, or to otherwise produce a clinicallyrecognizable change in the pathology of the disease or condition.

Pharmaceutical compositions can be prepared to allow a therapeuticallyeffective quantity of the compound of the present invention, and caninclude a pharmaceutically acceptable carrier, selected from knownmaterials utilized for this purpose. See, e.g., Remington, The Scienceand Practice of Pharmacy, 1995; Handbook of Pharmaceutical Excipients,3^(rd) Edition, 1999. Such compositions can be prepared in a variety offorms, depending on the method of administration.

In addition to the subject compound, the compositions of this inventioncan contain a pharmaceutically-acceptable carrier. The term“pharmaceutically-acceptable carrier”, as used herein, means one or morecompatible solid or liquid filler diluents or encapsulating substancesthat are suitable for administration to an animal, including a mammal orhuman. The term “compatible”, as used herein, means that the componentsof the composition are capable of being commingled with the subjectcompound, and with each other, such that there is no interaction thatwould substantially reduce the pharmaceutical efficacy of thecomposition under ordinary use. Preferably when liquid dose forms areused, the compounds of the invention are soluble in the components ofthe composition. Pharmaceutically-acceptable carriers must, of course,be of sufficiently high purity and sufficiently low toxicity to renderthem suitable for administration to the animal being treated.

Some examples of substances which can serve aspharmaceutically-acceptable carriers or components thereof are sugars,such as lactose, glucose and sucrose; starches, such as corn starchand-potato starch; cellulose and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powderedtragacanth; malt; gelatin; talc; solid lubricants, such as stearic acidand magnesium stearate; calcium sulfate; vegetable oils, such as peanutoil, cottonseed oil, sesame oil, olive oil, corn oil and oil oftheobroma; polyols such as propylene glycol, glycerine, sorbitol,mannitol, and polyethylene glycol; alginic acid; emulsifiers, such asthe Tween™ brand emulsifiers; wetting agents, such sodium laurylsulfate; coloring agents; flavoring agents; tableting agents,stabilizers; antioxidants; preservatives; pyrogen-free water; isotonicsaline; and phosphate buffer solutions. The choice of apharmaceutically-acceptable carrier to be used in conjunction with thesubject compound is basically determined by the way the compound is tobe administered. If the subject compound is to be injected, thepreferred pharmaceutically-acceptable carrier is sterile, physiologicalsaline, with a blood-compatible suspending agent, the pH of which hasbeen adjusted to about 7.4.

If the preferred mode of administering the subject compound isperorally, the preferred unit dosage form is therefore tablets,capsules, lozenges, chewable tablets, and the like. Such unit dosageforms comprise a safe and effective amount of the subject compound,which is preferably from about 0.7 or 3.5 mg to about 280 mg/70 kg, morepreferably from about 0.5 or 10 mg to about 210 mg/70 kg. Thepharmaceutically-acceptable carrier suitable for the preparation of unitdosage forms for peroral administration are well-known in the art.Tablets typically comprise conventional pharmaceutically-compatibleadjuvants as inert diluents, such as calcium carbonate, sodiumcarbonate, mannitol, lactose and cellulose; binders such as starch,gelatin and sucrose; disintegrants such as starch, alginic acid andcroscarmelose; lubricants such as magnesium stearate, stearic acid andtalc. Glidants such as silicon dioxide can be used to improve flowcharacteristics of the powder-mixture. Coloring agents, such as the FD&Cdyes, can be added for appearance. Sweeteners and flavoring agents, suchas aspartame, saccharin, menthol, peppermint, and fruit flavors, areuseful adjuvants for chewable tablets. Capsules typically comprise oneor more solid diluents disclosed above. The selection of carriercomponents depends on secondary considerations like taste, cost, andshelf stability, which are not critical for the purposes of thisinvention, and can be readily made by a person skilled in the art.

Peroral compositions also include liquid solutions, emulsions,suspensions, and the like. The pharmaceutically-acceptable carrierssuitable for preparation of such compositions are well known in the art.Such liquid oral compositions preferably comprise from about 0.012% toabout 0.933% of the subject compound, more preferably from about 0.033%to about 0.7%. Typical components of carriers for syrups, elixirs,emulsions and suspensions include ethanol, glycerol, propylene glycol,polyethylene glycol, liquid sucrose, sorbitol and water. For asuspension, typical suspending agents include methyl cellulose, sodiumcarboxymethyl cellulose, cellulose (e.g. Avicel™, RC-591), tragacanthand sodium alginate; typical wetting agents include lecithin andpolyethylene oxide sorbitan (e.g. polysorbate 80). Typical preservativesinclude methyl paraben and sodium benzoate. Peroral liquid compositionsmay also contain one or more components such as sweeteners, flavoringagents and colorants disclosed above.

Other compositions useful for attaining systemic delivery of the subjectcompounds include sublingual and buccal dosage forms. Such compositionstypically comprise one or more of soluble filler substances such assucrose, sorbitol and mannitol; and binders such as acacia,microcrystalline cellulose, carboxymethyl cellulose and hydroxypropylmethyl cellulose. Glidants, lubricants, sweeteners, colorants,antioxidants and flavoring agents disclosed above may also be included.

Compositions can also be used to deliver the compound to the site whereactivity is desired; such as eye drops, gels and creams for oculardisorders.

Compositions of this invention include solutions or emulsions,preferably aqueous solutions or emulsions comprising a safe andeffective amount of a subject compound intended for topical intranasaladministration. Such compositions preferably comprise from about 0.01%to about 10.0% w/v of a subject compound, more preferably from about0.1% to about 2.0%. Similar compositions are preferred for systemicdelivery of subject compounds by the intranasal route. Compositionsintended to deliver the compound systemically by intranasal dosingpreferably comprise similar amounts of a subject compound as aredetermined to be safe and effective by peroral or parenteraladministration. Such compositions used for intranasal dosing alsotypically include safe and effective amounts of preservatives, such asbenzalkonium chloride and thimerosal and the like; chelating agents,such as edetate sodium and others; buffers such as phosphate, citrateand acetate; tonicity agents such as sodium chloride, potassiumchloride, glycerin, mannitol and others; antioxidants such as ascorbicacid, acetylcystine, sodium metabisulfite and others; aromatic agents;viscosity adjustors, such as polymers, including cellulose andderivatives thereof; and polyvinyl alcohol and acids and bases to adjustthe pH of these aqueous compositions as needed. The compositions mayalso comprise local anesthetics or other actives. These compositions canbe used as sprays, mists, drops, and the like.

Other preferred compositions of this invention include aqueoussolutions, suspensions, and dry powders comprising a safe and effectiveamount of a subject compound intended for atomization and inhalationadministration. Such compositions are typically contained in a containerwith attached atomizing means. Such compositions also typically includepropellants such as chlorofluorocarbons 12/11 and 12/114, and moreenvironmentally friendly fluorocarbons, or other nontoxic volatiles;solvents such as water, glycerol and ethanol, these include cosolventsas needed to solvate or suspend the active; stabilizers such as ascorbicacid, sodium metabisulfite; preservatives such as cetylpyridiniumchloride and benzalkonium chloride; tonicity adjustors such as sodiumchloride; buffers; and flavoring agents such as sodium saccharin. Suchcompositions are useful for treating respiratory disorders, such asasthma and the like.

Other preferred compositions of this invention include aqueous solutionscomprising a safe and effective amount of a subject compound intendedfor topical intraocular administration. Such compositions preferablycomprise from about 0.01% to about 0.8% w/v of a subject compound, morepreferably from about 0.05% to about 0.3%. Such compositions alsotypically include one or more of preservatives, such as benzalkoniumchloride or thimerosal; vehicles, such as poloxamers, modifiedcelluloses, povidone and purified water; tonicity adjustors, such assodium chloride, mannitol and glycerin; buffers such as acetate,citrate, phosphate and borate; antioxidants such as sodiummetabisulfite, butylated hydroxy toluene and acetyl cysteine; acids andbases can be used to adjust the pH of these formulations as needed.

Other preferred compositions of this invention useful for peroraladministration include solids, such as tablets and capsules, andliquids, such as solutions, suspensions and emulsions (preferably insoft gelatin capsules), comprising a safe and effective amount of asubject compound. Such compositions can be coated by conventionalmethods, typically with pH or time-dependent coatings, such that thesubject compound is released in the gastrointestinal tract at varioustimes to extend the desired action. Such dosage forms typically include,but are not limited to, one or more of cellulose acetate phthalate,polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate,ethyl cellulose, Eudragit™ coatings, waxes and shellac.

The compounds of the invention are administered by ocular, oral,parenteral, including, for example, using formulations suitable as eyedrops. For ocular administration, ointments or droppable liquids may bedelivered by ocular delivery systems known to the art such asapplicators or eye droppers. Such compositions can include mucomimeticssuch as hyaluronic acid, chondroitin sulfate, hydroxypropylmethylcellulose or polyvinyl alcohol, preservatives such as sorbic acid,EDTA or benzylchromium chloride, and the usual quantities of diluentsand/or carriers. See, Remington's Pharmaceutical Sciences, 16th Ed.,Mack Publishing, Easton, Pa., 1980, as well as later editions, forinformation on pharmaceutical compounding.

Numerous additional administration vehicles will be apparent to those ofordinary skill in the art, including without limitation slow releaseformulations, liposomal formulations and polymeric matrices.

In another preferred embodiment, the pharmaceutically effective amountis approximately 0.1 or 0.5 to 4 mg/kg body weight daily. Still morepreferably, the pharmaceutically effective amount is approximately 1mg/kg body weight daily. In a preferred embodiment, the amount isadministered in once daily doses, each dose being approximately 1 mg/kgbody weight.

The activity of the compounds of the invention in breaking, reversing orinhibiting the formation of AGE's or AGE-mediated cross-links can beassayed by any of the methods described in U.S. Pat. No. 5,853,703.

The following examples further illustrate the present invention, but ofcourse, should not be construed as in any way limiting its scope.

EXAMPLE

Rats receive a daily intraperitoneal dose of 10 mg/kg of a compound ofthe invention (n=14) or placebo (n=15) for 30 days. The animals thenundergo a thoracotomy and the left anterior descending coronary arteryiss ligated. The chest is then closed and the animals allowed to recoverfor 14 days while continuing to be treated with compound or placebo. Theanimals are then sacrificed and the hearts removed for histologicalexamination. The weight of the infarcted tissue was is measured for theplacebo treated animals and compared to the weight for the compoundtreated animals. The thickness of the ventricular wall in the infarctedzone in compound-treated animals is compared to placebo.

Example 1

2,6-diamino-benzothiazole dihydrochloride: 4 g of2-amino-6-nitrobenzothiazole (Aldrich) was suspended in 130 ml MeOH, and0.4 g 10% Pd/C (Aldrich) added. The suspension was hydrogenated at roomtemperature under 60 psi H₂ for 6.5 h. The reaction mixture wasfiltered, and the particulate washed with MeOH. The filtrate wasconcentrated under reduced pressure, and crystals formed from theconcentrate were collected to yield 2.67 g, mp 196-198° C., yield 81.6%.0.91 g of this product was dissolved in 22 ml MeOH, and the pH adjustedwith HCl to 4 to produce 1.2 g of crystals of 2,6-diamino-benzothiazoledihydrochloride. mp 318-320° C., 92.3% yield. Anal. calc. forC₇H₉N₃SCl₂, C 35.30%, H 3.80%, N 17.64%. Found, C 34.91%, H 3.67%, N17.71%.

Example 2

2-(3,5-Dimethylphenoxy)-N-thiazol-2-yl)acetamide: First Route:3,5-Dimethylphenol is reacted with bromoacetic acid at 110° C. for fourhours, with the reaction mixture stirred overnight without added heat.The resulting (3,5-dimethylphenoxy)acetic acid is dissolved in methylenechloride and coupled to 2-aminothiazole in an overnight, roomtemperature reaction conducted in the presence of base(N-methylmorpholine) and dehydration mediators 1-hydroxybenzotriazoleand 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride.

Second Route: 3,5-Dimethylphenol is reacted for 4.5 h with bromoaceticacid in THF under nitrogen and in the presence of sodium hydride. Theresulting (3,5-dimethylphenoxy)acetic acid is reacted overnight withthionyl chloride, with heat. The resulting (3,5-dimethylphenoxy)acetylchloride is reacted overnight with 2-aminothiazole in the presence oftriethylamine, with cooling to 0° C.

Third Route: 2-Aminothiazole (20 g, 199.7 mmol) was suspended inmethylene chloride (200 ml), in the presence of pyridine (20 ml, ˜250mmol), and the mixture cooled to 0° C. Bromoacetyl bromide (18.1 ml,207.6 mmol) was dissolved in 400 ml methylene chloride, and thissolution added to the suspended 2-aminothiazole dropwise. The resultingreaction mixture was stirred at room temperature overnight. The crudeproduct was washed with water (200 ml, 1×), then sodium bicarbonatesolution (200 ml, 2×), dried over Na₂SO₄, filtered, and evaporated. Theproduct 2-bromoacetamidothiazole was crystallized from MeOH. Yield, 4 g,mp 148° C.

A solution of 3,5-dimethylphenol (2.5 g, 13.9 mmol) in dry DMF (20 ml)was placed under a dry nitrogen atmosphere. Sodium hydride (0.7 g, 27.8mmol; a 60% dispersion in mineral oil) was added in portions, and themixture stirred for 1 h. A solution of 2-bromoacetamidothiazole (3.0 g,13.9 mmol) in dry DMF (10 ml) was added to the mixture dropwise. Thereaction was heated to 90° C. for 5 h, then maintained overnight withoutexternal heat. The reaction mixture was poured into ice water, and theresulting material extracted with methylene chloride (50 ml×3). Theorganic layer was washed with water (100 ml×5), dried over Na₂SO₄,filtered, and evaporated. The residue from evaporation was purified bysilica gel chromatography developed with pet. ether: ether (1:1 v/v).The product 2-(3,5-dimethylphenoxy)-N-thiazol-2-yl)acetamide[N-(thiazolyl)-2-(3,5-dimethylphenoxy)-acetamide] was crystallized fromacetonitrile and methyl tert-butyl ether. Yield, 1.04 g, mp 124-125° C.

The compounds2-(3,5-dimethylphenoxy)-N-(4-methyl(1,3-thiazol-2-yl))acetamide,2-(3,5-dimethylphenoxy)-N-(5-methyl(1,3-thiazol-2-yl))acetamide,N-(4,5-dimethyl(1,3-thiazol-2-yl))-2-(3,5-dimethylphenoxy)acetamide,2-(3,5-dimethylphenoxy)-N-[5-(2-hydroxyethyl)-4-methyl(1,3-thiazol-2-yl)]acetamide,2-(3,5-dimethylphenoxy)-N-(5-chloro(1,3-thiazol-2-yl))acetamide,N-benzothiazol-2-yl-2-(3,5-dimethylphenoxy)acetamide,2-(3,5-dimethylphenoxy)-N-(5-bromo(1,3-thiazol-2-yl))acetamide,2-(3,5-dimethylphenoxy)-N-(4-phenyl(1,3-thiazol-2-yl))acetamide, ethyl2-[2-(3,5-dimethylphenoxy)acetylamino]-4-phenyl-1,3-thiazole-5-carboxylate,2-(3,5-dimethylphenoxy)-N-(5-nitro(1,3-thiazol-2-yl))acetamide,2-(3,5-dimethylphenoxy)-N-(6-nitrobenzothiazol-2-yl)acetamide, ethyl2-[2-(3,5-dimethylphenoxy)acetylamino]-1,3-thiazole-4-carboxylate,2-(3,5-dimethylphenoxy)-N-(1-methylimidazol-2-yl)acetamide,2-(3,5-dimethylphenoxy)-N-(1-methylbenzimidazol-2-yl)acetamide,2-(3,5-dimethylphenoxy)-N-[1-benzylbenzimidazol-2-yl]acetamide and2-(3,5-dimethylphenoxy)-N-(5-chlorobenzoxazol-2-yl)acetamide are made byone or more of the same methods, with the 2-amino heterocyclesubstituted as appropriate to obtain the product.

Example 3

2-Furyl-N-[4-(6-methyl-benzothiazol-2-yl)phenyl]carboxamide: FirstRoute: 2-Furoic acid (1.85 g, 16.5 mmole) was dissolved in anhydrousmethylene chloride (30 ml), to which solution was added a suspension of2-(4-amino-phenyl)-6-methyl benzothiazole (4.76 g, 16.5 mmole) andN-methyl morpholine (2.0 g, 16.5 mmole) in methylene chloride (30 ml, atroom temperature). Then, 1-hydroxy-benzotriazole hydrate (2.67 g, 16.5mmole) and 1-(3-dimethyl amino propyl)-3-ethyl carbodiimidehydrochloride (4.75 g, 16.5 mmole) were added at room temperature. Moremethylene chloride (20 ml.) was added with stirring at room temperature,and the reaction maintained overnight. The initial clear reactionsolution changed to a turbid solution. More methylene chloride (10 ml.)was added to the product mixture, which was then extracted with 1N HClto separate a solid. The solid was filtered and washed with water. Theproduct solid was crystallized from large amount of MeOH to yield 2.19 g(33.1%). mp 238-240° C. ¹H and ¹³C NMR were consistent with the expectedproduct. TLC showed one spot (5% MeOH—CH₂Cl₂ as developing solvent onsilica gel plate).

Route 2: 2-(4-aminophenyl)-6-methyl benzothiazole (2.0 g, 8.3 mmole) and2-Furoyl chloride (1.086 g, 8.32 mmole) were suspended in methylenechloride (30 ml, anhydrous). triethylamine (1.24 g, 12.25 mmole) wasadded to the reaction mixture with stirring at room temperature for 2days. (pH 7.0-7.2). Methylene chloride (50 ml) was added to the reactionmixture, and the reaction mixture extracted with 1 N HCl (50 ml) toseparate a solid. The solid was filtered and washed with water to yield1.3 g (46%) of the desired compound. The product was crystallized fromMeOH to obtain 0.99 g, mp 238-240° C. ¹H and ¹³C NMR were consistentwith the expected product. TLC showed one spot (5% MeOH—CH₂Cl₂ asdeveloping solvent on silica gel plate).

Definitions

Heterocycle. Except where heteroaryl is separately recited for the samesubstituent, the term “heterocycle” includes heteroaryl.

All publications and references, including but not limited to patentsand patent applications, cited in this specification are hereinincorporated by reference in their entirety as if each individualpublication or reference were specifically and individually indicated tobe incorporated by reference herein as being fully set forth. Any patentapplication to which this application claims priority is alsoincorporated by reference herein in its entirety in the manner describedabove for publications and references.

While this invention has been described with an emphasis upon preferredembodiments, it will be obvious to those of ordinary skill in the artthat variations in the preferred devices and methods may be used andthat it is intended that the invention may be practiced otherwise thanas specifically described herein. Accordingly, this invention includesall modifications encompassed within the spirit and scope of theinvention as defined by the claims that follow.

1. A compound of formula I or IA,

wherein: a. J is oxygen, sulfur, or N-R^(d); b. the carbon 2 to nitrogenbond is a double bond except when R^(c) is oxo; c. the bond betweencarbons 4 and 5 is a single bond or a double bond; d. R^(a) and R^(b)are
 1. independently selected from hydrogen, acylamino, acyloxyalkyl,alkanoyl, alkanoylalkyl, alkenyl, alkoxy, alkoxycarbonyl,alkoxycarbonylalkyl, alkyl, alkylamino, (C1-C3)alkylenedioxy, allyl,amino, ω-alkylenesulfonic acid, carbamoyl, carboxy, carboxyalkyl (whichalkyl can be substituted with alkyloxyimino), cycloalkyl, dialkylamino,halo, hydroxy, (C2-C6)hydroxyalkyl, mercapto, nitro, sulfamoyl, sulfonicacid, alkylsulfonyl, alkylsulfinyl, alkylthio, trifluoromethyl,morpholin-4-yl, thiomorpholin-4-yl, piperidin-1-yl, piperazin-1-yl, Ar{wherein, consistent with the rules of aromaticity, Ar is C₆ or C₁₀ arylor a 5- or 6-membered heteroaryl ring, wherein the 6-membered heteroarylring contains one to three atoms of N, and the 5-membered heterodrylring contains from one to three atoms of N or one atom of O or S andzero to two atoms of N, each heteroaryl ring can be fused to asubstituted benzene, pyridine, pyrimidine, pyridazine, or(1,2,3)triazine (wherein the ring fusion is at a carbon-carbon doublebond of Ar)}, Ar-alkyl, ArO—, ArSO₂—, ArSO—, ArS—, ArSO₂NH—, ArNH,(N—Ar)(N-alkyl)N—, ArC(O)—, ArC(O)NH—, ArNH—C(O)—, and (N—Ar)(N-alkyl)NC(O)—, or together R₁, and R₂ comprise methylenedioxy-, wherein at leastone of R^(a) and R^(b) is other than hydrogen; or
 2. together with theirring carbons form a C₆— or C₁₀-aryl fused ring; or
 3. together withtheir ring carbons form a C₅-C₇ fused cycloalkyl ring having up to twodouble bonds including a fused double bond of the containing group,which cycloalkyl ring can be substituted by one or more, of the groupconsisting of alkyl, alkoxycarbonyl, amino, aminocarbonyl, carboxy,fluoro, or oxo; or
 4. together with their ring carbons form a fused 5-or 6-membered heteroaryl ring, wherein the 6-membered heteroaryl ringcontains one to three atoms of N, and the 5-membered heteroaryl ringcontains from one to three atoms of N or one atom of O or S and zero totwo atoms of N; or
 5. together with their ring carbons form a fused fiveto eight membered second heterocycle, wherein the fused heterocycleconsists of ring atoms selected from the group consisting of carbon,nitrogen, oxygen, sulfur, and S(O)_(n), wherein n is 1 or 2; e. R^(d) isalkyl, alkenyl, hydrogen, or Ar; f. R^(c) is 1.dialkylamino(C₁-C₅)alkyl; or
 2. —NHC(O)(CH₂)_(n)-D-R^(e)R^(f), wherein Dis oxygen, sulfur or nitrogen, wherein where D is nitrogen n is 0, 1 or2, but when D is oxygen or sulfur n=1 or 2, and R^(f) is present onlywhen D is nitrogen, wherein (a) Re is (1) Ar, (2) a group of the formula

wherein E is sulfur, oxygen, or N—R^(i), and R^(g), R^(h) and R^(i) areindependently the same as R^(a), R^(b) and R^(d), respectively, (3) aC₃-C₈ cycloalkyl ring having up to one double bond with the proviso thatthe carbon linking the cyloalkyl ring to D is saturated, whichcycloalkyl ring can be substituted by one or more alkyl-,alkoxycarbonyl-, amino-, aminocarbonyl-, carboxy-, fluoro-, or oxosubstituents; or (4) a 5- or 6-membered heteroaryl ring containing atleast one, and up to three atoms of N for the 6-membered heteroarylrings and from one to three atoms of N or one atom of O or S and zero totwo atoms of N for the 5-membered heteroaryl rings; or (5) hydrogen,(C₂-C₆)hydroxyalkyl, alkanoylalkyl, alkyl, alkoxycarbonylalkyl, alkenyl,carboxyalkyl (which alkyl can be substituted with alkoxyimino),alkoxycarbonyl, a group Ar which is C₆— or C₁₀-aryl or a 5- or6-membered, or 9- or 10-membered heteroaryl (wherein the heteroatom isone oxygen, one sulfur or one nitrogen) or Ar^(Φ)-alkyl; and (b) R^(f)is independently hydrogen, (C2-C6)hydroxyalkyl, alkanoylalkyl, alkyl,alkoxycarbonylalkyl, alkenyl, carboxyalkyl (which alkyl can besubstituted with alkyloxyimino), alkoxycarbonyl, Ar^(Φ), orAr^(Φ)-alkyl; wherein aryl, Ar, or Ar^(Φ) can be substituted with, inaddition to any substitutions specifically noted one or moresubstituents selected from the group of acylamino, acyloxyalkyl,alkanoyl, alkanoylalkyl, alkenyl, alkoxy, alkoxycarbonyl,alkoxycarbonylalkyl, alkyl, alkylamino, (C1-C3)alkylenedioxy,alkylsulfonyl, alkylsulfinyl, ω-alkylenesulfonic acid, alkylthio, allyl,amino, ArC(O)—, ArC(O)NH—, carboxy, carboxyalkyl, cycloalkyl,dialkylamino, halo, trifluoromethyl, hydroxy, (C2-C6)hydroxyalkyl,mercapto, nitro, ArO—, Ar—, Ar alkyl-, sulfamoyl, sulfonic acid,1-pyrrolidinyl, 4-[C6 or C I O]arylpiperazin-1-yl-, 4-[C6 orClOlarylpiperidin-1-yl, azetidin-1-yl, morpholin-4-yl, thiomorpholin-4yl, piperazin-1-yl, piperidin-1-yl; and heterocycles, except those of Arand Ar^(Φ), can be substituted with in addition to any substitutionsspecifically noted one or more substituents selected from acylamino,alkanoyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, (C1 toC3)alkylenedioxy, alkylamino, alkylsulfonyl, alkylsulfinyl, alkylthio,amino, ArC(O)—, ArO—, Ar—, Ar-alkyl, carboxy, dialkylamino, fluoro,fluoroalkyl, difluoroalkyl, hydroxy, mercapto, oxo, sulfamoyl,trifluoromethyl, 4-[C₆ or C₁₀]arylpiperidin-1-yl and 4-[C₆ orC₁₀]arylpiperazin-1-yl.
 2. The compound of claim 1, wherein D is oxygenor sulfur.
 3. The compound of claim 2, wherein R^(e) is (1) Ar, (2) agroup of the formula

wherein E is sulfur, oxygen, or N—R^(i), and R^(g), R^(h) and R^(i) areindependently the same as R^(a), R^(b) and R^(d), respectively, (3) aC₃-C₈ cycloalkyl ring having up to one double bond with the proviso thatthe carbon linking the cyloalkyl ring to D is saturated, whichcycloalkyl ring can be substituted by one or more alkyl-,alkoxycarbonyl-, amino-, aminocarbonyl-, carboxy-, fluoro-, or oxosubstituents; or (4) a 5- or 6-membered heteroaryl ring containing atleast one and up to -three atoms of N for the 6-membered heteroarylrings and from one to three atoms of N or one atom of O or S and zero totwo atoms of N for the 5-membered heteroaryl rings.
 4. A compound offormula I or IA,

wherein: a. J is sulfur; b. R^(a) is hydroxyalkyl or alkylomega-substituted with a tertiary amine which is dialkyl amine or (i)incorporated into a 5- or 6-membered heteroaryl ring, wherein the6-membered heteroaryl ring contains one to three atoms of N, and the5-membered heteroaryl ring contains from one to three atoms of N or oneatom of O or S and one to two atoms of N or (ii) incorporated into a 5-or 6-membered non-aromatic heterocyclic ring having one to two ringnitrogens; and C. R^(b) and R^(c) are alkyl.
 5. A pharmaceuticalcomposition comprising an effective amount of a compound of claim
 4. 6.A compound of formula I or IA,

wherein: a. J is sulfur; b. the carbon 2 to nitrogen bond is a doublebond; c. the bond between carbons 4 and 5 is a double bond; d. R^(a) andR^(b) are independently selected from hydrogen, acylamino, alkanoyl,alkanoylalkyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl,(C2-C6)hydroxyalkyl, nitro, trifluoromethyl, Ar {wherein, Ar is C₆ orC₁₀ aryl}, or Ar-alkyl; and e. R^(c) is alkyl omega-substituted with atertiary amine which is dialkyl amine or (i) incorporated into a 5- or6-membered heteroaryl ring, wherein the 6-membered heteroaryl ringcontains one to three atoms of N, and the 5-membered heteroaryl ringcontains from one to three atoms of N or one atom of O or S and one totwo atoms of N or (ii) incorporated into a 5- or 6-membered non-aromaticheterocyclic ring having one to two ring nitrogens, wherein aryl can besubstituted with one or more substituents selected from the group ofacylamino, acyloxyalkyl, alkanoyl, alkanoylalkyl, alkenyl, alkoxy,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, (C₁-C₃)alkylenedioxy,alkylthio, allyl, carboxyalkyl, cycloalkyl, dialkylamino, halo,trifluoromethyl, hydroxy, (C₂-C₆)hydroxyalkyl, mercapto, nitro, ArO—,Ar—, or Ar-alkyl-.
 7. A pharmaceutical composition comprising aneffective amount of a compound of claim
 6. 8. A compound of formula I orIA,

wherein: a. J is sulfur; b. the carbon 2 to nitrogen bond is a doublebond; c. the bond between carbons 4 and 5 is a double bond; d. R^(a) andR^(b) are independently selected from hydrogen, acylamino, alkanoyl,alkanoylalkyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl,(C2-C6)hydroxyalkyl, nitro, trifluoromethyl, Ar {wherein, Ar is C₆ orC₁₀ aryl}, or Ar-alkyl; e. R^(c) is (C₂-C₅)alkyl omega-substituted withhalo, wherein aryl can be substituted with one or more substituentsselected from the group of acylamino, acyloxyalkyl, alkanoyl,alkanoylalkyl, alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl,alkyl, (C1-C3)alkylenedioxy, alkylthio, allyl, carboxyalkyl, cycloalkyl,dialkylamino, halo, trifluoromethyl, hydroxy, (C2-C6)hydroxyalkyl,mercapto, nitro, ArO—, Ar—, or Ar-alkyl-.